1 PROJECT SUMMARY 2 Alzheimer?s disease and related dementias (ADRD) are highly debilitating disorders and the prevalence is 3 expected to rise rapidly as the population ages. The causes of ADRD remain poorly understood, and there is a 4 critical need to identify novel modifiable risk factors as well as biological mechanisms of ADRD. Recent 5 epidemiological studies, including those published by investigators of the proposed study, suggest that age- 6 related impairment of the internal circadian clock may play a role in the development of ADRD in older men 7 and women. However it remains unclear what biological mechanisms may drive the associations between 8 weakened circadian rhythms and ADRD. Recent applications of metabolomics in epidemiological and clinical 9 studies suggest that there may be common metabolic pathways associated with both circadian disruption and 10 ADRD. This raises the possibility that age-related impairment in circadian rhythms may drive metabolic 11 changes, which in turn lead to the development of ADRD. This hypothesis is further supported by our exciting 12 metabolomics data from 50 men in the Osteoporotic Fractures in Men (MrOS) study: We found that both 13 weakened rest-activity rhythms and impaired cognitive function are associated with increases in ?-glutamyl 14 dipeptides, bile acids, fatty acids and acylcarnitines, but decreases in polyunsaturated fatty acids. Based on 15 the compelling data from epidemiological studies, as well as the intriguing findings from our metabolomics pilot, 16 we propose to comprehensively examine characteristics of the rest-activity rhythms and metabolomic profiles 17 in relation to long-term cognitive outcomes. Our metabolomics study will include 1500 older men and women 18 with 500 incident dementia cases from two unique and complimentary cohorts, the Women?s Health Initiative 19 and the MrOS. The current study includes three specific aims and one exploratory aim: Aim 1: Determine the 20 gender-specific relationships between rest-activity rhythms and long-term cognitive outcomes including ADRD 21 in older men and women. Aim 2: Identify metabolomics signatures that are associated with characteristics of 22 rest-activity rhythms and incident ADRD, respectively. Aim 3: Test whether common metabolites and pathways 23 mediate relationships between rest-activity rhythms and incident ADRD. For the Exploratory Aim, we will 24 examine the relationship between baseline rest-activity rhythms, changes in metabolomics markers, and long- 25 term cognitive outcomes in the subset of 300 MrOS participants with repeated serum samples. Our study is 26 innovative because it focuses on weakened circadian rhythms as a novel risk factor for ADRD. Moreover, it 27 goes beyond characterizing associations and focuses on identifying metabolic pathways linking rest-activity 28 rhythms with ADRD in a large population of free-living older adults. The proposed study is significant because 29 it has the potential to identify predictive and mechanistic biomarkers that may lead to better prevention, 30 diagnosis and treatment of ADRD.